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Loss of Rab11 synergizes with oncogenic Ras to alter growth and metabolism in intestinal cancer models

ABSTRACT: Cancer in the intestinal tract is governed by multiple pathways including Wnt, Ras, P53 and Hippo. The GTPase Rab11 regulates endosomal protein trafficking and in a previous report we showed that loss of Rab11 in enterocytes caused intestinal inflammation and hyperplasia in mice and flies. We show here that this inflammation may cooperate with cancer promoting pathways in the intestinal tract. First, lower Rab11 protein staining was observed in 63 out of 70 human colon cancer tissues and patients of age older than 70 had particularly consistent lower Rab11 level. Second, tissue specific knockout of Rab11a in the mouse intestinal epithelium enhanced the formation of intestinal adenocarcinoma after AOM feeding. Third, by using the Drosophila midgut as an experiment model, we show that loss of Rab11 synergizes with the oncoprotein RasV12 to promote cancer-related phenotypes. Fourth, the target genes of this synergistic interaction include the JAK-STAT pathway ligand Upd3 and the IGF pathway antagonist ImpL2. The expression of Upd3 promotes intestinal stem cell proliferation, while ImpL2 suppresses the metabolism of surrounding tissues. Our results demonstrate that a reduced Rab11 function may contribute to intestinal cancer progression by enhancing the growth and metabolic defects initiated by other tumor promoting pathways.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE92705 | GEO | 2019/12/21

REPOSITORIES: GEO

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Project description:Proteases constitute the largest enzyme gene family in vertebrates with intracellular and secreted proteases having critical roles in cellular and organ physiology. Intestinal tract contains diverse set of proteases mediating digestion, microbial responses, epithelial and immune signaling. Transit of chyme through the intestinal tract results in significant suppression of proteases. Although endogenous protease inhibitors have been identified, the broader mechanisms underlying protease regulation in the intestinal tract remains unclear. The objective of this study was to determine microbial regulation of proteolytic activity in intestinal tract using phenotype of post-infection irritable bowel syndrome, a condition characterized by high fecal proteolytic activity. Proteases of host pancreatic origin (chymotrypsin like pancreatic elastase 2A, 3B and trypsin 2) drove proteolytic activity. Of the 14 differentially abundant taxa, high proteolytic activity state was characterized by complete absence of the commensal Alistipes putredinis. Germ free mice had very high proteolytic activity (10-fold of specific-pathogen free mice) which dropped significantly upon humanization with microbiota from healthy volunteers. In contrast, high proteolytic activity microbiota failed to inhibit it, a defect that corrected with fecal microbiota transplant as well as addition of A. putredinis. These mice also had increased intestinal permeability similar to that seen in patients. Microbiota β-glucuronidases mediate bilirubin deconjugation and unconjugated bilirubin is an inhibitor of serine proteases. We found that high proteolytic activity patients had lower urobilinogen levels, a product of bilirubin deconjugation. Mice colonized with β-glucuronidase overexpressing E. coli demonstrated significant inhibition of proteolytic activity and treatment with β-glucuronidase inhibitors increased it. The findings establish that specific commensal microbiota mediates effective inhibition of host pancreatic proteases and maintains intestinal barrier function through the production of β-glucuronidases. This suggests an important homeostatic role for commensal intestinal microbiota.

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Loss of Rab11 synergizes with oncogenic Ras to alter growth and metabolism in intestinal cancer models

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